The invention relates to mesotetraphenylporphyrin complex compounds, new pharmaceutical agents containing these compounds, their use in diagnosis and therapy and processes for the production of these compounds and agents.
The use of complexing agents or complexes or their salts in medicine has been known for a long time. The following are examples:
Complexing agents as stabilizers of pharmaceutical preparations, complexes and their salts as adjuvants for the administration of poorly soluble ions (e.g., iron), complexing agents and complexes (preferably calcium or zinc), optionally as salts with inorganic and/or organic bases, as a poison antidote in the case of inadvertent incorporation of heavy metals or their radioactive isotopes and complexing agents as adjuvants in nuclear medicine using radioactive isotopes such as .sup.99m Tc for radionuclide imaging are known.
In patents EP 71564, EP 130934 and DE-OS 3401052, recently complexes and complex salts have been presented as diagnostic agents, primarily as NMR diagnostic agents.
These complexes and complex salts are tolerated quite well and guarantee as complete an excretion of the ions as possible. But they still do not optimally fulfill all criteria that determine the relative effectiveness of an NMR contrast medium, of which mainly the following are to be named:
a strong NMR activity (relaxivity), so that the contrast medium, in as low concentrations as possible, lowers the relaxation times of the protons in the tissue fluid and other nuclei such as P, F and Na in vivo and thus makes possible the localization of tumors by increasing the signal intensity of the image obtained with the aid of nuclear magnetic tomography; as selective as possible a concentration and/or retention of the contrast medium at the target organ or cancerous tissue; sufficient water solubility; low toxicity; good tolerability; good chemical and biochemical stability.
Here, relevant for the image production are above all both the first-mentioned points. Since the relaxations times among the tissues differ at most only by a factor of 2-3 (T. E. Budinger and P. C. Lauterbur, Sciences 226, pp 288-298, 1984;), J. M. S. Hutchinson and F. W. Smith in Nuclear Magnetic Resonance Imaging Edit. C. L. Partain et al., pp 231-249, Saunders, N.Y. 1983) and the complexes and complex salts of the patents mentioned generally are flawed by the drawback that they distribute themselves only relatively unspecifically in the extracellular space and thus are not always suitable for a recognition of pathologically changed tissues, there exists a need above all for selectively bonding, tumor-specific compounds that can be used in diagnosis.
Now it has been known for a few years that porphyrin derivatives concentrate selectively in human and animal tumors (D. Kessel and T.-H. Chou, Cancer Res. 43, pp 1994-1999, 1983, P. Hambright, Bioinorg. Chem. 5, pp. 87-92, 1975; R. Lipson et al., Cancer 20, pp. 2250-2267, 1957, D. Sanderson et al., Cancer 30, pp 1368-1372, 1972). The first attempts to use this class of compounds also as diagnostic agents have also been described (J. Winkelmann et al., Cancer Research 27, pp 2060-2064, 1967; European patent application publication number 133603; N. J. Patronas et al., Cancer Treatment Reports 70, pp 391-395, 1986). With these compounds (tetrakis(4-sulfonatophenyl)- and tetrakis(4-carboxylatophenyl)-porphyrin), only the manganese(III) ion has proven suitable as a paramagnetic metal.
But the compounds previously described are far from satisfactorily fulfilling the criteria mentioned above; particular attention is still to be paid to their insufficient concentration in the target organs. An improvement of this property at the same time should help reduce the existing problems with toxicity and tolerability of the previously known compounds.
Therefore there continues to be a need, for many purposes, for complex compounds that are stable, easily soluble but also better tolerated, selectively bonding, easily accessible, have available a wider range of chemical variations of substituents (which, e.g., make possible the incorporation of metals other than manganese or several, also different, metals and thus simultaneously lead to a control of the properties and uses of the compounds) and that are suited for diagnosis and/or also therapy of tumors.